The single most important advance in the last few years in the treatment of patients with osteolytic bone disease due to malignancy has been the approval by the FDA for use of pamidronate in patients with breast cancer metastatic to bone and in patients with myeloma, with or without hypercalcemia. However, data is now emerging which suggests that bisphosphonates have additional effects beyond those on bone resorption which have been completely unanticipated and unexpected. Studies of the behavior of human breast cancer cells which cause osteolytic bone disease in nude mice demonstrate that some bisphosphonates actually reduce tumor burden in bone as well as reducing osteolysis. Two separate studies in a relatively small number of patients treated with one bisphosphonate (clodronate) have suggested that the bisphosphonate decreases tumor burden in bone. Parallel animal studies also suggest that tumor cells may be more susceptible to chemotherapy in bisphosphonate-treated tumors. In vitro studies show that some bisphosphonates cause tumor cell detachment from bone surfaces and dramatic increases in apoptotic rates in tumor cells both in vitro and in vivo. These preliminary findings have extremely important implications for the treatment of patients with advanced cancers which affect bone. Some of the questions which are apparent are (1) are these effects related to particular bisphosphonates, (2) are these effects true for a range of different tumors, (3) are the effects of chemotherapeutic agents together with bisphosphonates independent of their mechanism of action, and (4) what is the mechanism responsible for bisphosphonates decreasing tumor burden, and in particular are these effects indirect, or are they direct and related to the capacity of bisphosphonates to cause apoptosis in vitro and in vivo. These questions are very difficult to address in patient studies. Patients with advanced cancer have many confounding variables which make interpretation of the data very difficult. It may take many years of multi- center studies to reach definitive conclusions. We plan to address these questions using a model of human breast cancer metastasis to bone that we have devised with the underlying hypothesis that the anti-tumor effects of certain bisphosphonates are related to their effects to cause apoptosis in tumor cells and osteoclasts. The data coming from this model should allow the rational planning of clinical studies with a high chance of definitive results.